Long-term results of isolated transmyocardial laser revascularization in combination with the intramyocardial autologous bone marrow stem cells injection.

To evaluate the long-term results of TMLR using a CO2 laser in combination with intramyocardial injection of ABMSC as an isolated procedure in patients with the end-stage coronary artery disease, the study included 20 patients (90% male), with a mean age of 58.4 ± 8.7 years. To assess the long-term results, patients were examined in a hospital. The Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Seattle Angina Questionnaire (SAQ) were used. The evolution of laboratory and instrumental indices, as well as medical therapy, was assessed. The end points of the study were death, acute myocardial infarction (AMI), repeated myocardial revascularization, recurrent hospitalizations due to coronary artery disease, and stroke. The changes in angina functional class were also evaluated. The median of follow-up period was 54 (36; 83) months, that is, 4.5 years. The analysis of the evolution of echocardiographic data showed the absence of statistically significant changes in the following parameters: left ventricular end-diastolic diameter (EDD) (p = 0.967), end-systolic diameter (ESD) (p = 0.204), end-diastolic volume (EDV) (p = 0.852), end-systolic volume (ESV) (p = 0.125), and left ventricular ejection fraction (LVEF) (p = 0.120). The patients continued to regularly take the main groups of medications. Nitrate consumption was significantly reduced (p < 0.001). Significant positive dynamics were observed in the changes in angina functional class. At the baseline, all patients had angina III FC, in the long term, 3 patients had II FC, 11 patients had I FC, and 6 patients had no angina. Clinical outcomes (mortality, recurrent myocardial infarction, stroke) were absent during the follow-up period. There were two cases of repeated myocardial revascularization. Regression analysis revealed that SYNTAX score was associated with the clinical outcome "repeated revascularization." TMLR in combination with intramyocardial injection of ABMSC is a safe method to achieve a statistically significant antianginal effect and reduce the need for "nitrates," which in turn improves the quality of life and reduces the frequency of hospitalizations due to coronary artery disease. These results can be achieved with strict adherence to the certain indications for the intervention.

Increased risks for random errors are common in outcomes graded as high certainty of evidence.

OBJECTIVES: The aim of article was to assess the risk for random errors in outcomes graded as high certainty of evidence (CoE). STUDY DESIGN AND SETTING: We randomly selected 100 Cochrane reviews with dichotomous outcomes rated as high CoE using Grading of Recommendations Assessment, Development, and Evaluation. To detect increased risks for random errors, two investigators independently conducted trial sequential analysis using conventional thresholds for type I (α = 0.05) and type II (ß = 0.10) errors. We dually regraded all outcomes with increased risks for random errors and conducted multivariate logistic regression analyses to determine predictors of increased risks for random errors. RESULTS: Overall, 38% (95% confidence interval: 28-47%) of high CoE outcomes had increased risks for random errors. Outcomes assessing harms were more frequently affected than outcomes assessing benefits (47% vs. 12%). Regrading of outcomes with increased random errors showed that 74% should have been downgraded based on current guidance. Regression analyses rendered small absolute risk differences (P = 0.009) and low number of events (P = 0.001) as significant predictors of increased risks for random errors. CONCLUSION: Decisionmakers need to be aware that outcomes rated as high CoE often have increased risks for false-positive or false-negative findings.

Ten-year follow-up after combined coronary artery bypass grafting and transmyocardial laser revascularization in patients with disseminated coronary atherosclerosis.

Coronary artery disease involving heavily calcified lesions has been associated with worse short- and long-term outcomes including increased mortality. This paper aims to evaluate long-term survival benefit when CABG + transmyocardial laser revascularization (TMLR) are performed on the hearts of patients with disseminated coronary atherosclerosis (DCA). This novel retrospective study was conducted between 1997 and 2002 and followed 86 patients with ischemic heart disease and severe DCA who underwent TMLR using a Holmium:YAG laser and/or CABG. There were 46 patients who had CABG plus TMLR on at least one heart wall ("combined therapy group") and 40 patients who had CABG or TMLR separately on at least one heart wall ("single therapy group"). For the whole group, actuarial survival at 10 years was 78.3% in the combined group compared to 72.5% in the single therapy group (p = 0.535). Ten-year survival in the combined vs. single therapy group for the anterior heart walls was 100 vs. 72.2% (p = 0.027). For the lateral and posterior heart walls were 73.7 vs. 73.3% (p = 0.97) and 84.2 vs. 72% (p = 0.27), respectively. Kaplan-Meier survival analysis showed benefit only for the anterior heart wall (F Cox test, p = 0.103). Single therapy procedures on all heart walls (odds ratio 1.736, p = 0.264) or on the anterior heart wall only (odds ratio 3.286, p = 0.279) were found to be predictors of 10-year late mortality. Combined therapy (TMLR + CABG) provides benefit for perioperative mortality and long-term survival only when provided on the anterior heart wall. For patients with disseminated coronary atherosclerosis, cardiac mortality was found to be increased when followed up 6 years later, regardless of the therapy applied.

Clinical outcomes meta-analysis: measuring subendocardial perfusion and efficacy of transmyocardial laser revascularization with nuclear imaging.

INTRODUCTION: Randomized and nonrandomized clinical trials have tried to assess whether or not TMR patients experience an increase in myocardial perfusion. However there have been inconsistencies reported in the literature due to the use of different nuclear imaging modalities to test this metric. The primary purpose of this meta-analysis was to determine whether SPECT, MUGA and PET scans demonstrate changes in myocardial perfusion between lased and non-lased subjects and whether laser type affects myocardial perfusion. The secondary purpose was to examine the overall effect of laser therapy on clinical outcomes including survival, hospital re-admission and angina reduction. METHODS: Sixteen studies were included in the primary endpoint analysis after excluding all other non-imaging TMR papers. Standardized mean difference was used as the effect size for all quantitative outcomes and log odds ratio was used as the effect size for all binary outcomes. RESULTS: Statistically significant improvements in myocardial perfusion were observed between control and treatment groups in myocardial perfusion at 6-month follow up using PET imaging with a porcine model. However non-significant differences were observed in patients at 3 and 12 months using SPECT, PET or MUGA scans. Both CO2 and Ho:YAG laser systems demonstrated an increase in myocardial perfusion however this effect was not statistically significant. In addition both laser types displayed statistically significant decreases in patient angina at 3, 6 and 12 months but non-significant increases in survival rates and decreases in hospital re-admissions. CONCLUSION: In order to properly assess myocardial perfusion in TMR subjects, subendocardial perfusion needs to be analyzed via nuclear imaging. PET scans can provide this level of sensitivity and should be utilized in future studies to monitor and detect perfusion changes in lased and non-lased subjects.

Video-assisted thoracoscopic surgery approach for transmyocardial laser revascularization.

Transmyocardial laser revascularization is an established therapy for refractory coronary artery disease. However, utilization of the technology is not as widespread as expected. This is despite the fact that the efficacy of the technology has been established in multiple prospective randomized trials. Furthermore, only about 5% of transmyocardial laser revascularization cases annually are performed in a minimally invasive fashion. We report a case of a female patient treated in a minimally invasive thoracoscopic fashion.

Long-term follow-up after Holmium:YAG laser revascularization combined with autologous bone marrow derived stem cells implantation.

Background: Coronary artery disease is a major cause of death worldwide. Despite different standard revascularization options, significant number of patients remains not suitable for any treatment. The aim of the study was to evaluate long-term outcome of patients with diffuse coronary artery disease, treated with autologous stem cells injections combined with transmyocardial laser revascularization. Material and Methods: 9 patients underwent Holmium:YAG laser revascularization and autologous bone marrow derived stem cells implantation between 2007 and 2009 in the Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Kraków and were subsequently followed up in 2015. Results: The mean follow-up period was 73 months. The mean CCS class significantly improved (1.4±0.5 vs 3.3±1.0; p<0.001) and cardiac related hospitalizations significantly decreased (1.1±0.8 vs 3.1±2.1; p<0.001). One death due to heart failure was observed. The mean LVEF increased from 38% to 42% (p>0.05). Conclusions: Clinical status improvement was observed with low mortality rate in the long-term follow-up. No new regional wall motion abnormalities were observed, and the increase of global ejection fraction was noted.

Transmyocardial Revascularization Enhances Bone Marrow Stem Cell Engraftment in Infarcted Hearts Through SCF-C-kit and SDF-1-CXCR4 Signaling Axes.

BACKGROUND: We investigated the roles of stem cell factor (SCF)-c-kit and stromal derived factor-1 (SDF-1)-CXCR4 signaling axes in transmyocardial revascularization (TMR)-enhanced engraftment of transplanted bone marrow stem cells (BMSCs) in infarcted hearts. METHODS: 3 weeks after LAD ligation, female Lewis rats underwent 10-channel needle-TMR, followed by daily IV injections of 1 million male donor BMSC for 5 days, either wild type (WT) or with knockdown (K/D) of c-kit or CXCR4, accomplished via a shRNA + plasmid in a lentiviral vector (N = 6/group). RESULTS: In our rat infarct model, 3 days after last BMSC injection, the number of BMSCs that homed into infarct was affected by both TMR and donor cell type, with greater BMSC engraftment with TMR and with WT BMSC (TMR, cell type, and interaction, P < 0.05). At 1 week, these differences persisted (TMR and cell type, P < 0.05). At 3 days, TMR significantly upregulated transcription of c-kit (TMR, p < 0.05), SCF (TMR and cell type, P < 0.05), CXCR4 (TMR and cell type, p < 0.05), and SDF-1 (TMR and cell type, P < 0.05). At 1 week, we saw similar declines in expression of c-kit (cell type, P < 0.05), SCF (TMR, P < 0.05), CXCR4 (TMR and cell type, P < 0.05), and SDF-1 (TMR, P < 0.05). At 1 week, TMR improved LV ejection fraction (LVEF) (N = 5) when WT BMSCs were infused, but knockdown of either c-kit or CXCR4 completely abrogated this TMR-mediated augmentation of BMSC reparative effect (TMR and cell type, P < 0.05). CONCLUSIONS: Downregulation of either c-kit or CXCR4 in BMSC decreased engraftment of circulating BMSC and inhibited reparative effects of TMR.

Alternative therapy for medically refractory angina: enhanced external counterpulsation and transmyocardial laser revascularization.

Medically refractory angina pectoris (RAP) is defined by presence of severe angina with objective evidence of ischemia and failure to relieve symptoms with coronary revascularization. Medication and invasive revascularization are the most common approaches for treating coronary artery disease (CAD). Although symptoms are eliminated or alleviated by these invasive approaches, the disease and its causes are present after treatment. New treatment approaches are needed to prevent the disease from progressing and symptoms from recurring. External enhanced counterpulsation therapy provides a treatment modality in the management of CAD and can complement invasive revascularization procedures. Data support that it should be considered a first-line treatment of RAP.

Combined use of transmyocardial laser revascularization and endothelial progenitor cells enhances neovascularization and regional contractility in a canine model of ischemic hearts.

The purpose of this study was to determine the combined effect of transmyocardial laser revascularization (TMLR) and the implantation of endothelial progenitor cells (EPCs) on cardiac function of ischemic hearts in canines. The left anterior descending artery (LAD) was occluded to establish the canine model of acute myocardial infarct (AMI). Four weeks later, the animals were randomly divided into four groups: TMLR group, in which transmyocardial laser-induced channels were established at the ischemic region; EPCs+TMLR group, in which EPCs were locally transplanted into laser-induced channels at the ischemic region; EPCs group, in which the EPCs were injected into the ischemic region; control group, in which the AMI animals received neither TMLR nor EPCs. The peripheral blood (50 mL) was sampled in all groups. Mononuclear cells from the peripheral blood were separated and cultured to obtain spindle-shaped attaching (AT) cells in vitro. AT cells were labeled with 1, 1'-dioctadecyl-1 to 3,3, 3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) before injecting into the laser-induced channels or ischemic region. Four weeks after the first operation, TMLR was performed in the TMLR group and EPCs+TMLR group, and at the same time, the EPCs originating from the AT cells were mixed with calcium alginate (CA). Then the EPCs-CA composites were implanted into myocardial channels induced by laser in the EPCs+TMLR group, and into the myocardial infarct area in the EPCs group. All dogs underwent echocardiography at second month after LAD occlusion. Finally the samples of myocardium around the LAD were subjected to histochemical and immunohistologic examinations. The results showed there was no significant difference in the diameter of left atrium and ventricle before treatment among all groups (P>0.05). Eight weeks after modeling, the regional contractility in the LAD territory in the EPCs+TMLR group was increased as compared with control group and TMLR group, but there was no significant difference between control group and TMLR group. Neoangiogenesis was observed in the EPCs+TMLR group, and the fibrosis was seen in the TMLR group. There was no significant difference in neoangiogenesis around the channels induced by laser among EPCs+TMLR, EPCs and TMLR groups. It was concluded that TMLR combined with EPCs could improve the regional and global cardiac function in AMI, and augment neovascularizaiton in channels of ischemic myocardium induced by laser.

Combined use of transmyocardial laser revascularization and endothelial progenitor cells enhances neovascularization and regional contractility in a canine model of ischemic hearts / 华中科技大学学报（医学）（英德文版）

The purpose of this study was to determine the combined effect of transmyocardial laser revascularization (TMLR) and the implantation of endothelial progenitor cells (EPCs) on cardiac function of ischemic hearts in canines. The left anterior descending artery (LAD) was occluded to establish the canine model of acute myocardial infarct (AMI). Four weeks later, the animals were randomly divided into four groups: TMLR group, in which transmyocardial laser-induced channels were established at the ischemic region; EPCs+TMLR group, in which EPCs were locally transplanted into laser-induced channels at the ischemic region; EPCs group, in which the EPCs were injected into the ischemic region; control group, in which the AMI animals received neither TMLR nor EPCs. The peripheral blood (50 mL) was sampled in all groups. Mononuclear cells from the peripheral blood were separated and cultured to obtain spindle-shaped attaching (AT) cells in vitro. AT cells were labeled with 1, 1'-dioctadecyl-1 to 3,3, 3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) before injecting into the laser-induced channels or ischemic region. Four weeks after the first operation, TMLR was performed in the TMLR group and EPCs+TMLR group, and at the same time, the EPCs originating from the AT cells were mixed with calcium alginate (CA). Then the EPCs-CA composites were implanted into myocardial channels induced by laser in the EPCs+TMLR group, and into the myocardial infarct area in the EPCs group. All dogs underwent echocardiography at second month after LAD occlusion. Finally the samples of myocardium around the LAD were subjected to histochemical and immunohistologic examinations. The results showed there was no significant difference in the diameter of left atrium and ventricle before treatment among all groups (P>0.05). Eight weeks after modeling, the regional contractility in the LAD territory in the EPCs+TMLR group was increased as compared with control group and TMLR group, but there was no significant difference between control group and TMLR group. Neoangiogenesis was observed in the EPCs+TMLR group, and the fibrosis was seen in the TMLR group. There was no significant difference in neoangiogenesis around the channels induced by laser among EPCs+TMLR, EPCs and TMLR groups. It was concluded that TMLR combined with EPCs could improve the regional and global cardiac function in AMI, and augment neovascularizaiton in channels of ischemic myocardium induced by laser.

The combined use of transmyocardial laser revascularisation and intramyocardial injection of bone-marrow derived stem cells in patients with end-stage coronary artery disease: one year follow-up.

BACKGROUND: There are a growing number of patients with end-stage coronary artery disease (CAD) and refractory angina. Angiogenesis may be induced by intramyocardial injection of autologous bone marrow stem cells, intensified by inflammation around channels performed by laser. AIM: To assess the effect of a combined treatment consisting of transmyocardial laser revascularisation (TLMR) and intramyocardial injection of bone-marrow derived stem cells (bone marrow laser revascularisation, BMLR) in patients with refractory angina one year after the procedure. METHODS: Five male patients (age 49-78 years) with end-stage diffuse CAD, severe angina (CCS III/IV) despite intensive medical therapy and disqualified from prior coronary artery bypass grafting (CABG) or percutaneous coronary intervention were included. After heart exposure, at sites where CABG was impossible, TMLR was performed with the Holmium: YAG laser combined with injection of 1 mL of bone marrow concentrate into the border zone of a laser channel using a Phoenix handpiece. RESULTS: No deaths in the follow-up period were observed. All patients were in I CCS Class. One year after the procedure,left ventricular (LV) segments treated by BMLR tended to demonstrate stronger myocardial thickening compared to baseline(53.0 ± 7.5% vs. 45.0 ± 9.5%; p = 0.06). Using late gadolinium-enhanced imaging, new myocardial infarction was found after one year only in one LV segment treated by BMLR. The BMLR treated regions in the remaining subjects, as well as regions subtended by left internal thoracic artery in two subjects, did not show new myocardial infarction areas. In contrast,all subjects who underwent only BMLR procedure revealed new and/or more extensive myocardial infarct in regions not treated by BMLR. CONCLUSIONS: Intramyocardial delivery of bone marrow stem-cells together with laser therapy is a safe procedure, with improvement in quality of life during follow-up. One year after the procedure, myocardial regions where BMLR was performed tended to demonstrate stronger myocardial thickening observed in cardiac magnetic resonance imaging.

Effects of transmyocardial jet revascularization with chitosan hydrogel on channel patency and angiogenesis in canine infarcted hearts.

The purpose of this study was to investigate whether transmyocardial jet revascularization (TMJR) with chitosan scaffolds retains channel patency and enhances angiogenesis after acute myocardial infarction (AMI) in a canine model. A total of 32 canines were randomly divided into four groups: myocardial infarction (MI), normal saline (NS), chitosan hydrogel (CH), and chitosan plus growth factor (CH + GF) groups. TMJR was performed surgically using a needle-free injector from the epicardium of canines in the NS, CH, and CH + GF groups; channels were filled with NS, CH, and CH + GF, respectively. After 6 weeks, the patency of the channels and angiogenesis around the channels were assessed by hematoxylin-eosin staining, immunohistochemistry, and Masson's trichrome staining. Results suggest that the channels in the CH and CH + GF groups may retain patency with luminal endothelization. Moreover, the vessel densities of the NS, CH, and CH + GF groups were significantly higher than that of the MI group, and that of the CH + GF group was the highest (p < 0.05). This study suggests that TMJR with chitosan scaffolds may help retain transmyocardial channel patency and enhance angiogenesis after AMI in canines.

La revascularización transmiocárdica con láser; una nueva vieja técnica. Pero ¿Es esfectiva? estudio retrospectivo sobre una cohorte de 453 pacientes / Transmyocardial revascularization with laser; a "new old Technique" but, is it useful? A study on a cohort of 453 patients

La cardiopatía isquémica, a pesar de las medidas higiénicas que se han tomado últimamente, sigue siendo una enfermedad de alta prevalencia en nuestro medio. Ello conlleva a que, tras tratamientos médico, quirúrgico y/o percutáneo, se tenga una cohorte de pacientes de difícil control médico y sin posibilidades intervencionistas. Para éste grupo de pacientes se ha desempolvado una antigua técnica ya descrita a inicios de los 60 del siglo XX, inspirada en el corazón de los reptiles, consistente en realizar perforaciones del miocardio en lo que se ha llamado revascularización transmiocárdica con láser (RTML). Sin embargo, al respecto de los resultados hay muchas opiniones encontradas. Para averiguar si en nuestro medio ésta técnica es útil, se ha revisado la historia de 453 pacientes intervenidos entre mayo de 1999 y noviembre de 2004. Se consideraron tres grupos que se denominaron Grupo I (53 pacientes), aquellos pacientes en los que no se pudo realizar revascularización quirúrgica completa y se complementó con RTML en los territorios no pontados, Grupo II (269 ptes.), aquellos que pudieron ser pontados en todos los vasos que lo necesitaban y Grupo III (130 ptes.), aquellos que no pudieron ser pontados en todos los vasos y no se hizo nada más. El seguimiento indicó que la necesidad de medicación no difería entre los tres grupos, la mortalidad tanto hospitalaria como en el seguimiento, tampoco se veía influida y sí parecía existir una mayor tendencia a agruparse en el grupo de mejor grado funcional cuando se aplicaba RTML. Concluimos que el tratamiento RTML no parece aportar grandes beneficios aunque no implique riesgos añadidos (AU)

Even after the application of higienical measures, ischemic cardiopathy is still a highly prevalent disease in our environment. After treating those patients medically, surgically and/or percutanously there will be a cohort of cases with difficult medical control and with no more possibilities. To treat those patients, an old technique, described at the beginning of the sixties of last century, and inspired in the heart of reptilians, has been recalled. This technique, called Transmyocardial Revascularization with Laser (TMRL), consists in piercing the whole myocardium with a laser beam. But the results are controversial. To discover the usefulness of this technique, a retrospective study on 453 operated on among may 1999 and november 2004 was performed. Three groups were considered: Group I (53 patients) formed by those patients not able to revascularize totally and complemented by TMRL in the areas not bypassed. Group II (269 pts) in which every patient could be completelyrevascularized. Group III (130 pts) in which those patients not able to be completely revascularized were just left without any more techniques. The follow-up indicated that the need of medication was not different among groups and the mortality in-hospital as well as in the follow-up, was similar in every group. The patients in group I were, in the long run, in a better functional class than in the other groups. So for we conclude that TMRL associated to surgical coronary by-pass does not implies better results but do not causes higher risks neither at the operation nor in the follow-up (AU)

Transmyocardial drilling revascularization combined with heparinized bFGF-incorporating stent activates resident cardiac stem cells via SDF-1/CXCR4 axis.

OBJECTIVE: To investigate whether transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor (bFGF)-incorporating degradable stent implantation (TMDRSI) can promote myocardial regeneration after acute myocardial infarction (AMI). METHODS: A model of AMI was generated by ligating the mid-third of left anterior descending artery (LAD) of miniswine. After 6 h, the animals were divided into none-treatment (control) group (n=6) and TMDRSI group (n=6). For TMDRSI group, two channels with 3.5 mm in diameter were established by a self-made drill in the AMI region, into which a stent was implanted. Expression of stromal cell-derived factor-1(α) (SDF-1(α)) and CXC chemokine receptor 4 (CXCR4), cardiac stem cell (CSC)-mediated myocardial regeneration, myocardial apoptosis, myocardial viability, and cardiac function were assessed at various time-points. RESULTS: Six weeks after the operation, CSCs were found to have differentiated into cardiomyocytes to repair the infarcted myocardium, and all above indices showed much improvement in the TMDRSI group compared with the control group (P<0.001). CONCLUSIONS: The new method has shown to be capable of promoting CSCs proliferation and differentiation into cardiomyocytes through activating the SDF-1/CXCR4 axis, while inhibiting myocardial apoptosis, thereby enhancing myocardial regeneration following AMI and improving cardiac function. This may provide a new strategy for myocardial regeneration following AMI.

Late angiograms ten years after transmyocardial laser revascularization.

We present the angiograms of a patient after transmyocardial laser revascularization (TMR), which were performed 10 years before by the application of holmium laser pulses. Thirteen years before the TMR procedure, the patient underwent coronary artery bypass graftings complicated by graft occlusion with no longer possibility of direct revascularization. Then, refractive angina required an alternative approach for symptom relief as the indirect revascularization by the application of the holmium laser pulses. Interestingly, the late angiograms, taken when the patient suffered from effort dyspnea for ongoing left ventricular dysfunction, showed a network of small vessels (absent before the TMR procedure) that supplies blood to the heart with no flow through the coronary arteries because of their complete occlusion. This is a historical presentation of the results of TMR to understand the effects of the indirect revascularization on the blood circulation through the heart over the long-term follow-up.